1. Field of the Invention
The present invention relates to processes for the preparation of 8-hydroxy-5-[(1R)-1-hydroxy-2[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone monohydrochloride. The present invention also relates to intermediates which are useful in such a process.
2. Discussion of the Background
8-hydroxy-5-[(1R)-1-hydroxy-2 [[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone monohydrochloride (I) is disclosed in EP 0 147 719 as a bronchodilator provided with a potent beta-2-adrenoceptor stimulating action.
The compound, that has also been referred to as 8-hydroxy-5-{(1R)-1-hydroxy-2-{N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride and TA 2005, is identified hereinafter for the sake of convenience also with the code CHF4226.

EP 0 147 719 describes a process for the preparation of TA2005, including within its scope all four optical isomers and mixture thereof. The process consists of the halogenation or oxidation of a compound of the formula (VII):
to give respectively a compound of the formula (VIII) or (IX), where X is halogen atom and Y′O— is hydroxyl or a conventionally protected hydroxyl,
which by reaction with N-(2-(p-methoxyphenyl)-1-methylethyl)-amine of formula (X)
gives a compound of formula (II′) or (III′):
which are reduced by reaction with a reducing agent to give the compound (IV′).

The compound (IV′) is obtained in the form of a mixture of two stereoisomers, (i.e., α- or β-isomers, constituted by a mixture of (R),(R)- and (S),(S)-isomers thereof or a mixture of (R),(S)- and (S),(R)-isomers thereof) that must be separated into each of the optical isomers of the compound (IV′) through a lengthy and time consuming method. Compound (I) is then obtained by the removal of the protecting group by catalytic hydrogenation of compound (IV′).
The process for the preparation of (I) according to Tanabe patent shows some problems and disadvantages. For example, compound (X) is considered a psychostimulant and hallucinogen, classified among psychotropic substances in many countries, therefore its preparation and use is regulated by very restrictive rules which makes its employment difficult without particular authorisations. Moreover, its preparation, disclosed on page 16, preparation 3 of EP 0 147 719, requires reagents of difficult preparation such as α-methyl-α-nitro-p-methoxystyrene and (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carboxylic acid.
In addition, the process for resolution, through fractional crystallization, seems quite difficult, especially for the use of many solvents or solvent mixtures, such as methanol, or ethyl acetate and isopropanol and of uncommon and expensive resolving agents, such as (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carboxilic acid. Furthermore, the reported yield, after crystallization, is very low, about 35%.
Moreover the synthesis of compound (I) according to EP 0 147 719 requires two hydrogenation steps, both carried out with catalytic Pd/C hydrogenation conditions to obtain (X) from its precursor, α-methyl-α-nitro-p-methoxystyrene and to deprotect the phenolic group during the conversion of (IV′) to (I).
Therefore there is a need to develop a process for the preparation of CHF4226 which does not have all the above mentioned drawbacks of the prior art and in particular there is a need to develop a process leading to the desired CHF4226 having the (R),(R) configuration.